Open AccessMultiple renal cancer susceptibility polymorphisms modulate the HIF pathway
Author(s) -
Steffen Grampp,
Virginia Schmid,
Rafik Salama,
Victoria Lauer,
Franziska Kranz,
James L. Platt,
James Smythies,
Hani Choudhry,
Margarete GoppeltStruebe,
Peter J. Ratcliffe,
David R. Mole,
Johannes Schödel
Publication year - 2017
Publication title -
plos genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.587
H-Index - 233
eISSN - 1553-7404
pISSN - 1553-7390
DOI - 10.1371/journal.pgen.1006872
Subject(s) - biology , hypoxia inducible factors , genetics , gene isoform , allele , gene , expression quantitative trait loci , transcription factor , cancer research , single nucleotide polymorphism , genotype
Un-physiological activation of hypoxia inducible factor (HIF) is an early event in most renal cell cancers (RCC) following inactivation of the von Hippel-Lindau tumor suppressor. Despite intense study, how this impinges on cancer development is incompletely understood. To test for the impact of genetic signals on this pathway, we aligned human RCC-susceptibility polymorphisms with genome-wide assays of HIF-binding and observed highly significant overlap. Allele-specific assays of HIF binding, chromatin conformation and gene expression together with eQTL analyses in human tumors were applied to mechanistic analysis of one such overlapping site at chromosome 12p12.1. This defined a novel stage-specific mechanism in which the risk polymorphism, rs12814794, directly creates a new HIF-binding site that mediates HIF-1α isoform specific upregulation of its target BHLHE41 . The alignment of multiple sites in the HIF cis -acting apparatus with RCC-susceptibility polymorphisms strongly supports a causal model in which minor variation in this pathway exerts significant effects on RCC development.